This Program Project focuses on the mechanisms that contribute to arterial diseases in five projects that span from basic work on vascular molecular biology to study of intact human subjects. Each component project addresses the theme, Arterial Dysfunction, sharing several common aspects, among them inflammation and oxidative stress as pathogenic mechanisms and altered functions of cells, particularly the endothelium, as prime contributors to arterial dysfunction related to prevalent human diseases. Inflammatory and Infectious Mechanisms in Atherogenesis, Peter Libby and Andrew Lichtman, Project Leaders, will examine molecular mechanisms by which Chlamydia pneumoniae may potential atherogenesis and elicit a vascular immune response. Mechanisms of Oxidant Induced Arterial Inflammation, James K. Liao, Project Leader will study how oxidative stress may regulate endothelial gene expression focusing particularly on the inhibitors of NF-kappaB, on NADH oxidase, and on the Metabolic Syndrome, Jorge Plutzky, Project leader, will address the roles of the PPAR family of transcription factors in regulation of genes involved in aspects of arterial dysfunction associated with insulin resistance. Mechanisms of Arterial Dysfunction in Diabetes, Mark A. Creager, Project Leader, will probe the mechanisms of the defect in arterial function he found in human diabetics during the initial funding period, by evaluating the roles of protein kinase Cbeta, PPARgamma,, and glutathione peroxidase activity. Mechanisms of Altered Vasoreactivity in Diseased arteries, Peter Ganz and Andrew Selwyn, Project Leaders, will examine the role of endothelin regulation of tone in diseased coronary and pulmonary arteries in intact humans. Two cores will support the proposed research (Administration, Peter Libby, Core Director, Vascular Pathology, Frederick J. Schoein, Core Director.) The project leaders have all cooperated closely for many years, and work in contiguity. The integrated basic and clinical approaches we propose emphasizing novel mechanisms of arterial dysfunction, should continue to furnish new insights into the pathogenesis and treatment of cardiovascular and pulmonary diseases.